1. Field of the Invention
This invention relates to optically active pyrrolopyridazine derivatives of formula (I) or pharmaceutically acceptable salts thereof.
This invention further relates to pharmaceutical compositions comprising an optically active pyrrolopyridazine derivative of formula (I) or a pharmaceutically acceptable salt thereof (preferably compositions for prevention or treatment of an ulcerative disease) as an active ingredient.
In another aspect, this invention relates to the use of an optically active pyrrolopyridazine derivative of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition (preferably a composition for the prevention or treatment of an ulcerative disease).
In another aspect, this invention relates to a method for the prevention or treatment of disease (preferably an ulcerative disease), which method comprises administering a pharmaceutically effective amount of an optically active pyrrolopyridazine derivative of formula (I) or a pharmaceutically acceptable salt thereof to a warm-blooded animal (preferably a human) in need of such treatment.
In yet another aspect, this invention relates to a process for the preparation of optically active pyrrolopyridazine derivatives of formula (I) and pharmaceutically acceptable salts thereof.
2. Background Information
It has been considered that an imbalance between aggressive factors and protective factors against the gastric mucous membrane induces a peptic ulcer. Gastric acid secretion is an aggressive factor and suppression of gastric acid secretion is useful in the prevention and treatment of the disease. Anticholinergic drugs, histamine H2 receptor antagonists such as cimetidine and proton-pump inhibitors such as omeprazole have been clinically used as a gastric acid secretory inhibitor. Although these drugs are excellent therapeutic agents for ulcerative disease, the disease may recur after cessation of the therapy. It has been recently reported that Helicobacter pylori relates to the recurrence of the ulcerative disease. Actually there have been some attempts to use a gastric acid secretory inhibitor in combination with an antibacterial ag for treatment of the disease.
Accordingly a compound that exhibits potent gastric acid secretory inhibition activity, excellent gastric mucous membrane protection activity and potent antibacterial activity against Helicobacter pylori would be expected to be an excellent prophylactic and therapeutic agent for gastric ulcer disease.
Some pyrrolopyridazine derivatives that have gastric acid secretory inhibition activity and protect gastric mucous membranes have been described in U.S. Pat. No. 6,063,782, WO 91/17164, WO 92/06979 and WO 93/08190. In Japanese Patent Application Publication Hei 7-247285 the activity against Helicobacter pylori of some pyrrolopyridazine derivatives has also been described.
The inventors have continued an investigation on the pharmacological activities of pyrrolopyridazine derivatives in order to discover compounds that exhibit potent gastric acid secretory inhibition activity, protect gastric mucous membranes and have excellent antibacterial activity against Helicobacter pylori for a long time. It was proved that some optically active pyrrolopyridazine derivatives substituted with a trans-alkylcyclopropylmethyl group have such activities and are superior to the corresponding racemate as a medicament.
This invention relates to optically active pyrrolopyridazine derivatives of formula (I) hereinbelow or pharmaceutically acceptable salts thereof.
This invention further relates to pharmaceutical compositions comprising an optically active pyrrolopyridazine derivative of formula (I) or a pharmaceutically acceptable salt thereof (preferably compositions for prevention or treatment of ulcerative disease) as an active ingredient.
In another aspect, this invention relates to the use of an optically active pyrrolopyridazine derivative of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition (preferably a composition for the prevention or treatment of ulcerative disease).
In another aspect, this invention relates to a method for the prevention or treatment of a disease (preferably an ulcerative disease), which method comprises administering a pharmaceutically effective amount of an optically active pyrrolopyridazine derivative of formula (I) or a pharmaceutically acceptable salt thereof to a warm-blooded animal (preferably a human) in need of such treatment.
In yet another aspect, this invention relates to a process for the preparation of optically active pyrrolopyridazine derivatives of formula (I) and pharmaceutically acceptable salts thereof.
An optically active pyrrolopyridazine derivative of the present invention has the following formula: 
wherein:
R1 is a C1-C6 alkyl group;
R2 and R3 are each independently a C1-C6 alkyl group;
R4 is a C6-C10 aryl group which is optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogeno C1-C6 alkyl, C1-C6 alkoxy, halogeno C1-C6 alkoxy and halogen; and
A is an imino group, an oxygen atom or a sulfur atom.
The C1-C6 alkyl moiety of the alkyl group in the definitions of R1, R2, R3 and R4 and of the halogeno C1-C6 alkyl, C1-C6 alkoxy and halogeno C1-C6 alkoxy group included in the definition of R4 is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl or hexyl group; is preferably a C1-C4 alkyl group; more preferably a methyl or ethyl group and most preferably methyl.
The halogen atom included in the definition of R4 is, for example, a fluorine, chlorine, bromine or iodine atom; preferably a fluorine, chlorine or bromine atom and more preferably a fluorine or chlorine atom.
The C6-C10 aryl group in the definition of R4 is, for example, a phenyl or naphthyl group; preferably a phenyl group. The number of substituents on the aryl group is from 1 to 5; 1 to 3 is preferable, 1 or 2 is more preferable and 1 is the most preferable. The C6-C10 aryl group is optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogeno C1-C6 alkyl, C1-C6 alkoxy, halogeno C1-C6 alkoxy and halogen is preferably, for example, a phenyl, methylphenyl, (trifluoromethyl)phenyl, methoxyphenyl, (trifluoromethoxy)phenyl, (difluoromethoxy)phenyl, fluorophenyl, chlorophenyl, bromophenyl, difluorophenyl, chlorofluorophenyl, dichlorophenyl, trifluorophenyl, trichlorophenyl, naphthyl, methylnaphthyl, methoxynaphthyl, fluoronaphthyl, chloronaphthyl or bromonaphthyl group; more preferably a phenyl, 4-methylphenyl, 4-(trifluoromethyl)phenyl, 4-methoxyphenyl, 4-(trifluoromethoxy)phenyl, 4-(difluoromethoxy)phenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 4-bromophenyl, 2,4- or 2,6-difluorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4- or 2,6-dichlorophenyl, 2,4,6-trifluorophenyl or 2,4,6-trichlorophenyl group; more preferably a 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl or 2,4-dichlorophenyl group; most preferably a 4-fluorophenyl or 4-chlorophenyl group.
A is preferably an oxygen or sulfur atom, more preferably an oxygen atom.
The pharmaceutically acceptable salt of the compound of formula (I) is an acid addition salt, for example, a hydrohalogenic acid salt such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; a nitrate; a perchlorate; a sulfate; a phosphate; a carbonate; a C1-C6 alkylsulfonate which is optionally substituted with fluorine atom(s), such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, pentafluoroethanesulfonate, propanesulfonate, butanesulfonate, pentanesulfonate and hexanesulfonate; a C6-C10 arylsulfonate such as benzenesulfonate and p-toluenesulfonate; a carboxylate, such as acetate, propionate, butyrate, benzoate, fumarate, maleate, succinate, citrate, tartrate, oxalate and malonate; or an amino acid salt such as glutamate and aspartate; preferably a hydrochloride, sulfate or carboxylate; more preferably a hydrochloride.
The compound of formula (I) of the present invention or a salt thereof can exist as a hydrate form and the scope of the present invention encompasses the hydrate form.
Preferred compounds of formula (I) of the present invention include:
(1) a compound wherein R1 is a C1-C4 alkyl group;
(2) preferably a compound wherein R1 is a methyl group;
(3) a compound wherein R2 and R3 are each independently a C1-C4 alkyl group;
(4) preferably a compound wherein R2 and R3 are each methyl groups;
(5) a compound wherein R4is a phenyl group substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, halogeno C1-C4 alkyl, C1-C4 alkoxy, halogeno C1-C4 alkoxy, fluoro, chloro and bromo;
(6) preferably a compound wherein R4is a phenyl group substituted with 1 to 3 substituents selected from the group consisting of methyl, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, fluoro, chloro and bromo;
(7) more preferably a compound wherein R4 is a phenyl group substituted at the 2-, 4- and/or 6-positions with 1 or 2 substituents selected from the group consisting of fluoro and chloro,
(8) most preferably a compound wherein R4 is a phenyl group substituted at the 4-position with a substituent selected from fluoro or chloro or a phenyl group substituted at the 2- and 4-positions with two substituents selected from the group consisting of fluoro and chloro;
(9) a compound wherein A is an oxygen atom or a sulfur atom; and/or
(10) more preferably compound wherein A is an oxygen atom.
Preferred compounds of formula (I) also include compounds wherein R1 is selected from the group consisting of (1) and (2), R2 and R3 are selected from the group consisting of (3) and (4), R4 is selected from the group consisting of (5), (6), (7) and (8) and A is selected from the group consisting of (9) and (10).
Such compounds include, for example,
(11) a compound wherein R1 is a C1-C4 alkyl group, R2 and R3 are each independently C1-C4 alkyl groups, R4 is a phenyl group substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, halogeno C1-C4 alkyl, C1-C4 alkoxy, halogeno C1-C4 alkoxy, fluoro, chloro and bromo, and A is an oxygen atom or a sulfur atom;
(12) preferably a compound wherein R1 is a methyl group, R2 and R3 are each methyl groups, R4 is a phenyl group substituted with 1 to 3 substituents selected from the group consisting of methyl, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, fluoro, chloro and bromo, and A is an oxygen atom or a sulfur atom;
(13) more preferably a compound wherein R1 is a methyl group, R2 and R3 are each methyl groups, R4 is a phenyl group substituted at the 2-, 4- and/or 6-positions with 1 or 2 substituents selected from the group consisting of fluoro and chloro, and A is an oxygen atom; and
(14) most preferably a compound wherein R1 is a methyl group, R2 and R3 are each methyl groups, R4 is a phenyl group substituted at the 4-position with a substituent selected from fluoro or chloro or a phenyl group substituted at the 2- and 4-positions with two substituents selected from the group consisting of fluoro and chloro, and A is an oxygen atom.
Table 1 typically exemplifies preferable compounds of formula (I).
In Table 1, the symbols Me and Ph denote the methyl and phenyl groups respectively.
The preferred compounds in Table 1 are those of exemplification compound number 1, 2, 4, 5, 7, 9, 10, 11, 13, 17, 18, 19, 21, 22, 23, 24, 25, 28, 29, 30, 31, 32, 34, 37 and 38;
the more preferred compounds are those of 1, 4, 5, 7, 9, 10, 17, 18, 21, 22, 24, 25, 31, 32 and 34;
the still more preferred compounds are those of 4, 5, 9, 10, 21, 22 and 24; and the most preferred compounds are
4: 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine;
5: 7-(2,4-difluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine; and
9: 7-(4-chlorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine.
The pyrrolopyridazine derivatives of formula (I) can be prepared by the method rated in the following reaction scheme. 
In the formulae of the compounds in the above reaction scheme, R1, R2, R3, R4 and A are as defined above, R5 is a C1-C6 alkyl group, R6 is a hydrogen atom or a formyl group, X is a halogen atom (preferably a chlorine, bromine or iodine atom) or a C1-C6 alkanesulfonyloxy or C6-C10 arylsulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, butanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy and naphthalenesulfonyloxy (preferably a methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy group) and Y is a halogen atom (preferably a chlorine, bromine or iodine atom).
Step 1, in which a compound of formula (IV) is prepared, is accomplished by reaction of a compound of formula (II) with a compound of formula (III) in an inert solvent in the presence of a base. When R6 is a hydrogen atom, this is followed by formylation of the reaction product.
The base used in the reaction of the compound of formula (II) with the compound of formula (III) is, for example, an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; an alkali metal amide such as lithium amide, sodium amide or potassium amide; an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; an alkali metal alkoxide such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium tert-butoxide; an organic amine derivative such as triethylamine, tributylamine, diisopropylethylamine, N-ethylmorpholine, pyridine, picoline, 4-(N,N-dimethylamino)pyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); is preferably an alkali metal hydride (especially sodium hydride) or an alkali metal alkoxide (especially potassium tert-butoxide).
The inert solvent in step 1 is not limited provided that it has no adverse effect on the reaction and can dissolve the starting materials to a certain extent. Such a solvent is, for example, an aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether; an aromatic hydrocarbon such as benzene, toluene or xylene; a halogeno-hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; a ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone; an amide such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; a sulfoxide such as dimethylsulfoxide; or sulfolane; or mixtures thereof; and is preferably an ether (especially tetrahydrofuran or dioxane).
The reaction temperature of step 1 is usually in the range of from 0xc2x0 C. to 250xc2x0 C. (preferably from room temperature to 150xc2x0 C.). The reaction time of step 1 depends on the reaction temperature and the like and is in the range of from 1 minute to 50 hours (preferably from 10 minutes to 30 hours).
A quaternary ammonium salt such as benzyltrimethylammonium chloride, tetrabutylammonium chloride or tetrabutylammonium bromide or a crown ether such as 18-crown-6 or dibenzo-18-crown-6 may be added to the reaction mixture in order to effectively carry out the reaction.
When R6 is hydrogen, the subsequent formylation of the product obtained by the reaction of the compound of formula (II) with the compound of formula (III) is accomplished by reaction of the product with a Vilsmeier reagent in the presence or absence of an inert solvent.
The Vilsmeier reagent is known in the chemistry arts and is, for example, a combination of a halogenating reagent and dimethylformamide such as phosphorus oxychloride-dimethylformamide, phosphorus oxybromide-dimethylformamide or oxalyl chloride-dimethylformamide, and is preferably phosphorous oxychloride-dimethylformamide.
The inert solvent in the Vilsmeier reaction is not limited provided that it has no adverse effect on the reaction and can dissolve the starting materials to a certain extent. Such a solvent is, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; a halogeno-hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; or an amide such as dimethylformamide, and is preferably a halogeno-hydrocarbon (especially methylene chloride, chloroform or dichloroethane).
The reaction temperature for the Vilsmeier reaction is usually in the range of from xe2x88x9220xc2x0 C. to 150xc2x0 C. (preferably from 0xc2x0 C. to 100xc2x0 C.). The reaction time depends on the reaction temperature and the like and is in the range of from 15 minutes to 12 hours (preferably from 30 minutes to 5 hours).
Step 2, in which a compound of formula (V) is prepared, is accomplished by a reaction of a compound of formula (IV) with hydrazine or a hydrate thereof in an inert solvent.
The inert solvent used in step 2 is not limited provided that it has no adverse effect on the reaction and can dissolve the starting materials to a certain extent. Such a solvent is, for example, an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; an alcohol such as methanol, ethanol, propanol or isopropanol; an aromatic hydrocarbon such as benzene, toluene or xylene; a carboxylic acid such as acetic acid or propionic acid; an amide such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphorictriamide; an amine such as triethylamine or pyridine; water; or mixtures thereof, and is preferably an alcohol (especially ethanol) or a carboxylic acid (especially acetic acid).
The reaction temperature of step 2 is usually in the range of from xe2x88x9250xc2x0 C. to 150xc2x0 C. (preferably from xe2x88x9210xc2x0 C. to 120xc2x0 C.). The reaction time of step 2 depends on the reaction temperature and the like and is in the range of from 10 minutes to 12 hours (preferably from 30 minutes to 5 hours).
Step 3, in which a compound of formula (VI) is prepared, is accomplished by reaction of a compound of formula (V) with a halogenating reagent in the presence or absence of an inert solvent.
The halogenating reagent in this step is, for example, phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus pentachloride or phosphorus pentabromide, preferably phosphorus oxychloride or thionyl chloride. A large excess of the halogenating reagent can be used as a solvent in this step.
The inert solvent in step 3 is not limited provided that it has no adverse effect on the reaction and can dissolve the starting materials to a certain extent. Such a solvent is, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; a halogeno-hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; an amide such as dimethylformamide, dimethylacetamide or N-methyl-2-pyrrolidone; or a sulfoxide such as dimethylsulfoxide; and is preferably a halogeno-hydrocarbon (especially methylene chloride or dichloroethane).
The reaction temperature of step 3 is usually in the range of from 0xc2x0 C. to 150xc2x0 C. (preferably from room temperature to 120xc2x0 C.). The reaction time of step 3 depends on the reaction temperature and the like and is in the range of from 30 minutes to 12 hours (preferably from 1 hour to 6 hours).
An organic amine derivative such as triethylamine, tributylamine, diisopropylethylamine, N-ethylmorpholine, pyridine, picoline or 4-(N,N-dimethylamino)pyridine may be added to the reaction mixture in order to effectively carry out the reaction.
Step 4, in which a desired compound of formula (I) of the present invention is prepared, is accomplished by reaction of a compound of formula (VI) with a compound of formula (VII) in the presence of a base in an inert solvent in a similar procedure to that described in step 1.
Each desired product of steps 1, 2, 3, and 4 may be isolated by conventional procedures from the reaction mixture. For example, it may be obtained 1) by filtration of the reaction mixture when insoluble material exists in the reaction mixture, followed by evaporation of the solvent of the filtrate; or by 1) concentration of the reaction mixture, 2) partition of the residue between water and an appropriate organic solvent immiscible with water, 3) drying the extract over anhydrous magnesium sulfate and the like, followed by 4) concentration of the extract. The desired compound is, if necessary, further purified by conventional procedures such as recrystallization, column chromatography and the like.
The desired optically active compound (1S and 2S configuration) can also be prepared by optical resolution of the racemic product (the racemic form of the compound of any one of formulae (I), (IV), (V) or (VI)), which is obtained by the same procedure using the racemic compound of formula (IIIa) (a mixture of 1S, 2S and 1R, 2R configuration) in step 1 instead of the optically active compound of formula (IIIa). 
A method of optical resolution can be appropriately selected from conventional procedures, for example, column chromatography for optical resolution, preferential crystallization, or resolution of diastereomeric salts.
The compound of formula (I) can be converted into its pharmaceutically acceptable salt by treatment with an acid. For example, it can be obtained by reaction of the compound of formula (I) with an acid in an inert solvent (a preferred solvent is an ether such as diethyl ether, tetrahydrofuran or dioxane; an alcohol such as methanol, ethanol or propanol; or a halogeno-hydrocarbon such as methylene chloride or chloroform) for from 5 minutes to 1 hour, followed by concentration.
The starting compounds of formulae (II), (III) and (IIIa) are known or prepared by methods known to the skilled person (for example, Japanese Patent Application Publication Hei 7-247285, Monatschefte fur Chemie 104, 925 (1973), J. Chem. Soc. Perkin. Trans. II 287 (1979) and the like).
The compounds of formula (I) of this invention exhibit potent gastric acid secretion inhibition activity, protective activity of gastric mucous membranes and potent antibacterial activity against Helicobacter pylori and excellent properties as a medicament. The compounds of formula (I) are useful as a medicament, especially a useful prophylactic or therapeutic (preferably therapeutic) agent for ulcerative diseases such as peptic ulcer, acute or chronic gastric ulcer, gastritis, reflux esophagitis, gastroesophageal reflux disorder, dyspepsia, gastric hyperacidity or Zollinger-Ellison syndrome, and as a prophylactic or therapeutic (preferably therapeutic) agent for bacterial infections arising from Helicobacter pylori. 
When used as a medicament, especially as a prophylactic or therapeutic agent for the diseases described above, a compound of formula (I) or a pharmaceutically acceptable salt thereof (the active ingredient) can be administered alone or can be presented as part of a pharmaceutical formulation. The pharmaceutical formulation is prepared by blending the active ingredient with appropriate pharmaceutically acceptable carriers such as excipients, diluents and the like, followed by formulation in the form of tablets, capsules, granules, powders or syrups and the like for oral administration or in the form of injections and the like for parenteral administration (preferably oral administration).
The production of such pharmaceutical formulations is carried out according to general techniques known to those skilled in the art, using additives such as an excipient, a binder, a disintegrant, a lubricant, a stabilizer, a corrigent, a diluent and a solvent for injections.
The excipient is, for example, a sugar derivative such as lactose, sucrose, glucose, mannitol or sorbitol; a starch derivative such as corn starch, potato starch, xcex1-starch, dextrin or carboxymethyl starch; a cellulose derivative such as crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose or internally bridged sodium carboxymethyl cellulose; gum arabic; dextran; pullulan; a silicate derivative such as light silicic acid anhydride, synthetic aluminium silicate or magnesium aluminate meta-silicate; a phosphate derivative such as calcium phosphate; a carbonate derivative such as calcium carbonate; or a sulfate derivative such as calcium sulfate; and the like.
The binder is, for example, one of the excipients described above; gelatin; polyvinylpyrrolidone; macrogol (trademark) and the like.
The disintegrant is, for example, one of the excipients described above, a chemically modified starch or cellulose derivative such as sodium croscarmellose, sodium carboxymethyl starch; or bridged polyvinylpyrrolidone; and the like.
The lubricant is, for example, talc; stearic acid; a metal salt of stearic acid such as calcium stearate or magnesium stearate; colloidal silica; a wax such as bee gum and spermaceti; boric acid; glycol; a carboxylic acid such as fumaric acid or adipic acid; a sodium carboxylate such as sodium benzoate; a sulfate such as sodium sulfate; leucine; a laurylsulfate such as sodium laurylsulfate and magnesium laurylsulfate; a silicic acid derivative such as silicic acid anhydride or silicic acid hydrate; one of the starch derivatives described above in relation to the excipients; and the like.
The stabilizer is, for example, a p-hydroxybenzoate derivative such as methylparaben and propylparaben; an alcohol such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; a phenol derivative such as phenol or cresol; thimerosal; dehydroacetic acid; sorbic acid; and the like.
The corrigent is, for example, a sweetening, souring or flavoring agent, which are conventionally used; and the like.
The solvent for injection is, for example, water, ethanol, glycerin and the like.
Suitable dosage levels will depend on the condition of disease, the age of the patient and the like, but typically suitable dosage levels for an active ingredient of the present invention are from 1 mg (preferably 5 mg) to 1000 mg (preferably 500 mg) for oral administration and from 0.1 mg (preferably 1 mg) to 500 mg (preferably 300 mg) for intravenous administration per unit dose, per day, for an adult human, respectively. The dosages described above are preferably administered from one time to six times throughout the day, depending on the condition of disease.